1. IMPORTANCE, APPLICATION, FACTORS AFFECTING DISSOLUTION RATE, THEORIES OF DISSOLUTION & OFFICIAL DISSOLUTION TESTS

2. INTRODUCTION
Dissolution is defined as the process by which a solid substance enters in the solvent to yield a solution OR
Dissolution is the process by which a solid substance dissolved OR
Fundamentally, it is controlled by the affinity between the solid substance and solvent.

3. IMPORTANCE & APPLICATION
Dissolution testing evaluated critical parameter such as
Predict adequate bioavailability
Help to avoid batch to batch variation
QC and IPQC test.
Selection of best formulation &comparison of excipient effect on dosage form
In vivo – in vitro co-relation
Regulatory requirement of official test
F1 & F2 (similarity dissimilarity) value help to get comparing dissolution pattern of test with market product
A.N.D.A. & N.D.A. required dissolution test.
Sometimes modification is also required for better invivo predictability:

4. FACTORS AFFECTING DISSOLUTION RATE
SIX MAIN CLASSES
Factor related to the physicochemical property of the drug
Factor related to drug product formulation
Factor related to dosage form
Factor related to dissolution testing device
Factor related to dissolution test parameters
Miscellaneous factor

5. Factor related to physicochemical property
Solid phase characteristics
Amorphicity & crystallinity
Amorphous form of drug usually greater solubility &higher dissolution rate as compared to crystalline form.

6. Co precipitation &/or Complexation
Polymorphism
Co precipitation &/or Complexation
Co precipitation as well as complexation are use for enhancing the dissolution rate of drug due to,
Formation energetic amorphous drug phase or
Drug being molecularly dispersed or
Formation of co accervates
e.g. Hydroflumethiazide – PVP co precipitate has four times more solubility than crystalline drug.

7. Particle size
If the drug hydrophobic reduction in particle size may lead to decrease in effective surface area and hence slower the rate of dissolution.

8. Salt formation
by salt formation to increase the solubility

9. Factor Related To Drug Product Formulation (Solid Dosage Form)
Diluent & Disintegrant
Studies of starch on dissolution rate of salicylic acid tablet
excipient dilution (drug/excipient ratio).

10. Granulating agent and Binder
e.g. Phenobarbital tablet granulated with gelatin solution, Na – carboxymethyl cellulose or polyethylene glycol 6000 as binder.
Also depend on conc. of binder.
Water soluble granulating agent Plasdone give faster dissolution rate than with gelatin. .

11. Disintegrating agent Lubricants
Studies of various disintegrating agents on Phenobarbital tablet
Lubricants

12. Effect of certified water – soluble dyes on the dissolution rate
Surfactant
e.g. treated cassava starch with SLS/polysorbate – 80 in sulfadiazine tablet
Effect of certified water – soluble dyes on the dissolution rate
Effect of coating component on tablet dissolution

13. Factor Related To Dosage Form
Manufacturing procedure (granulation)
Granule size

14. Drug excipient interaction
The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate
Compression force
The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet
1. tighter bonding
2. higher compression force cause deformation crushing or fracture of drug particle or convert a spherical granules into disc. Shaped particle
3.& 4. both condition

15. Deaggregation Storage of dosage form
Deaggregation is prerequisite for dissolution
Deaggregation controls the rate of dissolution
Storage of dosage form

16. Factor Related To The Dissolution Testing Device
Agitation
Agitation changes hydrodynamic condition & flow pattern
Relation ship between intensity of agitation & rate of dissolution.
K = a (N) b
Where N = speed of agitation
K = dissolution rate
a & b are constant

17. Stirring element alignment
Vibration
The speed of rotation device officially 100 rpm.
Periodical variation in rpm might result in possible disturbance in rotational acceleration this phenomenon is known as torsional vibration.
Stirring element alignment
The USP / NF XV states that the axis of the stirring element must not deviate more than 2 mm from the axis of the dissolution vessel
Tilt in excess of may increase dissolution rate from 2 to 25%.

18. Flow pattern disturbance
The geometry and alignment of stirring device, external vibration rotational speed, thermometer, distance of basket or paddle from the lowest point of the bottom of the round bottom flask are affecting on the flow pattern.
Sampling Probe, Position & Filter
Sampling probe can affect the hydrodynamic of the system
Position of sampling, USP / NF state that sample should be removed at approximately half the distance from the basket or paddle to the dissolution medium and not closer than 1 cm to the side of the flask
Filter material must be saturated with the drug by repeated passage to avoid losses that might go undetected during the test sampling.

19. Factor Related To Dissolution Test Parameter
Temperature
USP /NF specifies that the dissolution medium must be held at 370C (±0.5) & for topical (320±0.5).
Dissolution medium
Effect of dissolution air on dissolution medium
Altering PH
Dissolved air tends to release slowly in form of tiny air bubble that circulate randomly and affect hydrodynamic flow pattern
Specific gravity decrease thus floating of powder thus wetting and penetration problem.
Dissolution media composition & PH
Addition of Na – sulfate decrease the dissolution rate.
Addition of urea increase dissolution rate.

20. Various Official Dissolution Test
Solid dosage form (tablet & capsule)
I.P. & E.P.
Apparatus I – paddle apparatus
Apparatus II – basket apparatus
B.P. & U.S.P.
Apparatus I – basket apparatus
Apparatus II – paddle apparatus
B.P. & E.P.
Apparatus III – flow through cell apparatus
Conditions ( for all)
Temp. - 37±0.50C
PH - ±0.05 unit in specified monograph
Capacity – 1000 ml
Distance between inside bottom of vessel and paddle/basket is maintained at 25±2 mm.

22. Apparatus III – Reciprocating cylinder
Consist of a cylindrical , that bottom vessel that accommodate a glass reciprocating cylinder whose end are close with a polypropylene mesh screen.
The dosage unit placed in reciprocating cylinder & the release of drug into solvent within the cylinder measured.
Apparatus IV – flow through cell
Used flow though cell with a filter system, through which the dissolution medium is pumped.
Temp. for both apparatus III & IV at 37±0.50C.

24. Apparatus V – Paddle over disk.
The disk assembly design to minimize to any dead volume.
The disk assembly is located at 25±2 mm from the bottom the paddle.
Apparatus VI – cylinder
Used basket apparatus except that the basket and shaft are replaced with a stainless steel cylinder stirring element.
Apparatus VII – (reciprocating holder )
Use solution container in which a specifically designed disk sample holder may be made to reciprocating.
For apparatus V,VI&VII
Procedure carried out at 32±0.50 C. (because deliver system are used on the skin)

26. Model dependent and model independent method to compare dissolution profile with similarity and dissimilarity factors
Approach
Method
Parameter/equation
Model-independent
Ratio test procedures
Ratio of percent dissolved
Ratio of are under dissolution curve
Ratio of mean dissolution time
Pair wise procedures
Difference factor (f1)
Similarity factor (f2)
Model-dependent
Zero-order
% diss = kt
First-order
% diss = 100 (1 – e-kt)
Hixson-Crowell
% diss = 100 [1-(1- kt/ mg1/3) 3
Higuchi
% diss = kt0.5
Quadratic
% diss = 100(k1t2 + k2t)
Weibull
% diss = 100 [1 – e- (t/)]
Gompertz
% diss = A e-e-k (t-)
logistic
% diss = A / [1+e-k(t-)]

27. If difference is small then it is acceptable.
GRAPHICAL METHOD
In this method we plot graph of Time V/S concentration of solute (drug) in the dissolution medium or biological fluid.
Higher differences indicate that the dissolution profile is not comparable.
If difference is small then it is acceptable.
If two or more curves are overlapping then the dissolution profile is comparable

29. DETERMINING DISSOLUTION PROFILE SIMILARITY
A minimum of 12 dosage units must be evaluated .
similarity factor (f2).
similar when the f2 value is _50.
To allow the use of mean data, the coefficient of variation should not be more than 20% at the earlier time points (e.g., 10 minutes), and should not be more than 10% at other time points.
Note :-When both test and reference products dissolve 85% or more of the label amount of the drug in 15 minutes using all three dissolution media recommended above, the profile comparison with an f2 test is unnecessary

30. Similarity factor, f2
This is the most simple model independent mathematical approach to compare dissolution profile.
Where Rt & Tt are cumulative % dissolved at of selected n points of reference & test product respectively.

31. Press coated
TIME
REFERENCE A
R1-F1
(R1-F1)2 30 60 90
120
150
2.32
1.9
180
2.42
210
2.52
3.02
240
4.22
4.08
270
4.18
4.26
300
6.24
5.88
330
100.28
98.98
360
99.98
99.92
390
100.25
100.1

32. TIME
REFERENCE A
R1-F1
(R1-F1)2 30 60 90
120
150
2.35
0.98
180
1.98
210
2.55
2.44
240
4.26
3.85
270
4.2
4.44
300
7.21
7.34
330
100.02
98.22
360
98.64
99.1
390
98.85
100.2

33. THEORIES OF DISSOLUTION
Several theories to explain drug dissolution
Diffusion layer model / film theory
Dankwert‘s model / penetration or surface renewal theory
Interfacial barrier model / double barrier or limited salvation theory

34. Diffusion layer model / film theory
This process of dissolution by diffusion with out reactive or chemical force
Consist of two consecutive steps
Solution of the solid to form a thin film or layer at the solid / liquid interface called as stagnant film or diffusion layer which is saturated with the drug this step is usually rapid (instantaneous).
Diffusion of the soluble solute from the stagnant layer to the bulk of the solution this step is slower and is therefore the rate determine step in the drug dissolution.

35. Equation (A) is based on fick’s first law of diffusion & constant surface area

36. Brunner incorporated fick’s first law of diffusion and modification of the Noyes – Whitney’s equation to

37. Sink condition
In vivo condition, there is no conc. build up in the bulk of the solution and hence no retarding effect on the dissolution rate of the drug i.e. Cs>>Cb and sink condition maintain.

39. Sink condition can be achieved by,
Bathing the dissolving solid in fresh solvent from time to time.
Increase the volume of dissolution fluid.
Removing the dissolved drug by the organic phase e.g. hexane or chloroform.
Adding a water miscible solvent such as alcohol
By adding selected adsorbents to remove the dissolution drug.
Noyes Whitney’s equation assumes that surface area should remain constant during the dissolution.

40. Hixson and Crowell’s cubic root low of dissolution for change in surface area on dissolution due to decrease in particle and decrease in surface area.
W01/3 – W1/3 = kt
W0 = original mass of drug
W = mass of drug remaining to dissolve at time t
K = dissolution rate constant

41. Dankwert’s Model (Penetration Or Surface Renewal Theory)
This model assume that transport of solute away from the solid surface is achieve by means the agitated fluid consisting of macroscopic mass of eddies or packets reach the solid/liquid interface in a random fashion due to eddy currents.

42. Interfacial barrier model (double barrier or limited salvation theory
Based on salvation mechanism & solubility rather than diffusion.
The interfacial barrier model can be extended to both diffusion layer model and the Dankwert’s model.

43. Introduction to BCS and dissolution study

44. INTRODUCTION OF BCS
BCS provides a scientific approach for classifying dug compounds based on solubility as related to dose and intestinal permeability in combination with dissolution properties oral immediate release dosage forms.
According to BCS, drugs are classified into four classes.

45. Class I : High solubility – High permeability
These drugs exhibits high absorption number and high dissolution number.
Rate limiting step is gastric emptying rate.
Class II : Low solubility – High permeability
Absorption for class II drugs is usually slower than class I and occurs over a longer period of time.
Rate limiting step is in-vivo drug dissolution.

46. Class III : High solubility – Low permeability
Here permeability is the rate limiting step for absorption.
Since the dissolution is rapid, the variation is attributed to alteration of physiology and membrane permeability rather than dosage form factors.
Class IV : Low solubility - Low permeability
This drugs exhibits lots of problems for effective oral administration.

47. Solubility enhancement
Possibilities of shifting the solubility – dissolution characteristics form a very poorly soluble drug to D.S within the range of values encountered in the Human GI track
Absorption enhancing excipient, Lipid filled capsule, GI motility consideration
Prodrugs, Salt form, Cosolvent, Solubilization by Surfactants, Micro-particles, Liposome, Lyophilization
Particle size reduction, Soluble salts, Self emulsifying system, Solid dispersion, Addition of surfactants, Nanoparticles, Cyclodextrine complex, pH adjustment, Salting out I
III II IV
Solubility enhancement
Permeation enhancer

48. AIM OF BCS
To provide regulatory tool for replacing certain bioequivalence studies by accurate in-vitro dissolution tests.
This will reduce the cost in drug development process, also reduce unnecessary drug exposure in healthy objects.
To provide guidance for industry.

49. BASIC REQUIREMENTS OF BCS
It must predict the in-vivo dissolution system well.
Rate limiting step for in-vivo absorption must be well defined.
Limits for permeability and solubility must be balanced.
In-vitro methods should be sufficiently robust for correct classification.

50. PROBLEMS WITH BCS
Every chances of misclassification.
It is based on highest dose what about smaller doses of same product.
Today it is intended only for IR products that are absorbed through out intestinal tract.

51. Industrial implementation OF BCS
Since class- I drugs are having high solubility & permeability, their biowaiver request is granted by FDA.
Potential Cost Savings.
To examine this number of BE studies performed by industry per year was examined.
Indirect Savings.
-time saving
-clinical resources are freed to be applied elsewhere.

52. CLASS BOUNDARIES Highly soluble when highest dose strength is
soluble in 250 ml or less water over
a pH range of 1 to 7.5
Highly permeable when extent of intestinal absorption
is 90 % or higher.
Rapidly dissolving when not less than 85% of labeled
amount of drug substance dissolves
within 30 min using USP apparatus I
at 100 rpm in volume of 900 ml or less in
each of following media
(1) 0.1 N HCL or USP simulated gastric fluid without enzymes.
(2) a 4.5 pH buffer
(3) a 6.8 pH buffer or simulated intestinal fluid USP without enzymes.

53. SOLUBILTY DETERMINATION
By pH – solubility profile of test drug in aqueous media with a pH range of 1 to 7.5
Shake flask or titration method.
Analysis by validated stability indicating assay.

54. PERMEABILITY DETERMINATION
Extent of absorption in humans:
Mass-balance pharmacokinetic studies.
Absolute bioavailability studies.
Intestinal permeability methods:
In vivo intestinal perfusions studies in humans.
In vivo intestinal perfusion studies in animals.
In vitro permeation experiments with excised human or animal intestinal tissue.
In vitro permeation experiments across epithelial cell monolayer
The most common in-vitro cell culture technique used to assess permeability is the CaCo –2 ( human colon carcinoma ) cell live or sub-clone ( e.g. Tc-7) based estimates .

55. SUGGESTED IMPROVEMENTS OF BCS
BCS could be reduced into two classes.
Class-I Permeation rate limited absorption:
Drugs with in-vivo Kdiss > in-vivo Kpe belong to class I regardless fa.
Class-II Dissolution rate limited absorption:
Drugs with in-vivo Kdiss< in-vivo Kpe belong to class II.
Here in-vivo BE studies are required.

56. Bcs containing six classes
Bergstrom et al. carried out a study, in which BCS containing six Classes was used,
Solubility was classified as “high” or “low”
Permeability was classified as “low”, “intermediate” or “high”.

57. Gohel suggested third dimension to BCS, i.e. chiral conversion.
Class
Solubility
Permeability
Chiral Conversion I
High
A High*
B Low* II
Low
A High
B Low
III IV

58. Research Gate
Case Studies 1: We demonstrated in vivo bioequivalence between the pilot batch and the reference product. We did the dissolution test of the pilot batch using the dissolution conditions specified in the FDA database, and we obtained slightly lower results. When we run the dissolution test with peak vessels, the results show some improvement. Can we use peak vessels in this case?
Case Studies 2: What dissolution medium can be used with poorly water-soluble drugs (BCS Class 2)? If the drug substance is not soluble in that medium, how should the standard solutions for the calibration curve be prepared?
Case Studies 3: Which solvents can be employed to prepare the standard solution to be used in the quantitative procedure in dissolution testing? Is it mandatory to use the dissolution medium?
Case Studies 4: I am preparing a film containing sumatriptan. How should I select the composition of the dissolution medium?
Case Studies 5: Most of the dissolution tests use 900 mL of medium. How was this volume defined? Is there any correlation with the volume of gastric fluid in humans?

59. Case Studies 6: I am working with a gastroretentive drug delivery system for a fixed combination product. Drug A has absorbance in 0.1 N HCl while drug B does not. Can I use two separate media for the fixed combination product, 0.1 N HCl for drug A and water for drug B?
Case Studies 7: We are developing a floating tablet, and it remains floating in the dissolution vessel during the entire test. Is it mandatory that the tablet should remain on the bottom of the dissolution vessel?
Case Studies 8: I am working on a project to enhance the solubility of a drug that is insoluble in water. I am uncertain on how to develop the dissolution test; I would like to use phosphate buffer as dissolution medium, but the drug is not soluble in this buffer.
Case Studies 9: Is a dissolution test needed for the active substance as a single component in a capsule dosage form, or would a disintegration test be adequate?
Case Studies 10: How is the dissolution sample solution determined? We find that in some tests, the samples withdrawn from the vessel need to be diluted as part of the quantitative procedure.

60. BIOWAIVERS
Means to waive off doing bioavailability and bioequivalence studies.
Conditions for justifying request of biowaiver .
Drug must be highly soluble & permeable.
Must be stable in GIT.
Product is designed not to be absorbed in oral cavity.
Must not have narrow therapeutic index.
Excipients used in IR solid dosage forms must have no significant effect on rate & extent of oral drug absorption .

61. BIOWAIVER EXTENSIONS (1) For class II drugs:
Here in-vivo dissolution is rate limiting step.
If in-vivo dissolution can be estimated in vitro, it is possible to establish IVIVC.
But experimental methods are difficult to design & validate because no. of in-vitro process involved.
Key determinant for class II drug absorption is the solubility in the absorbing region of intestine.

62. So, change in formulation is required.
Add SLS to mimic solubilization in vitro and maintenance of sink condition in vivo resulting from continuous absorption.
Addition of various surfactants concentration in dissolution media may be adequate for quality control but not sufficient for predicting in-vivo dissolution.

63. (2) For class III drugs:
drugs shows permeability limited absorption
It has been contended that there are equally compelling reasons to grant biowaivers to class III drugs as class I drugs.
If the dissolution of class III drugs is rapid under all physiological pH conditions, it is expected that they will behave like oral solution in-vivo and in-vivo bioequivalence study is generally waived off for oral solutions.

64. Recent survey of FDA data of over 10 BCS class III drugs shows that most commonly used excipients in oral solid dosage forms have no significant effect on absorption.
Class III drug products containing significant amount of GIT transit affecting or permeability changing excipient should be excluded from consideration of biowaivers.

65. SLS, fatty acids, steroidal detergents changes membrane permeability.
For E.g..
SLS, fatty acids, steroidal detergents changes membrane permeability.
Mannitol, sorbitol can reduce small intestine transit time.
Isoniazid which lies at borderline of BCS class I & III. Its biowaiver is recommended when the test product meets WHO requirements for “Very rapidly dissolving” and contains only excipients commonly used in isoniazid products.

66. BIORELEVANT DISSOLUTION MEDIA
Biorelevant in vitro dissolution testing is useful for qualitative forecasting of formulation and food effects on dissolution and availability of orally administered drug.
It is used to ensure that the in vitro test mimic the in vivo as closely as possible.
This media can provide more accurate simulation of pharmacokinetic profiles than SGF or SIF.

67. Fasted state simulated intestinal fluid
Fed state simulated intestinal fluid
Sodium taurocholate
Lecithin
NaOH (pellets)
Sodium Dihydrogen Phosphate
Nacl
Purified water
PH-6.5 and osmolality- 270 mOsmol/kg
Glacial Acetic Acid
PH-5.00 and osmolality- 670 mOsmol/kg

68. DISSOLUTION MEDIA
Primary require for selection of dissolution media is that, it should be able to reflect in vivo situations when it is used to establish an IVIVC
For Class I and III drugs, use of simple aqueous media such as SGF without enzymes or SIF without enzymes is recommended.
For Class II and III drugs, use of biorelevant media for dissolution testing is recommended.
They are: 1) SGF plus surfactant
2) Milk with 3.5 % fat to
stimulate fed state condition
3)FaSSIF is used for poorly
soluble drugs.

69. PH of the dissolution medium.
Factors affecting selection of dissolution medium.
PH of the dissolution medium.
Surface tension of dissolution medium.
Viscosity of the dissolution medium.
Presence of uncreative and reactive additives in the dissolution medium.
Volume of the dissolution medium and sink conditions.